JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS

Volume 30, Number 10, 2014

ª Mary Ann Liebert, Inc.
DOI: 10.1089/jop.2014.0040

Gatifloxacin 0.5% Administered Twice Daily

for the Treatment of Acute Bacterial Conjunctivitis
in Patients One Year of Age or Older

Warren Heller,1 Marilou Cruz,2 Yasmin Rusi Bhagat,3 Jesse M. De Leon,4 Carlos Felix,5
Linda Villanueva,5 David A. Hollander,5 and Harold Jensen 5

Abstract

Purpose: To evaluate the efficacy and safety of gatifloxacin 0.5% ophthalmic solution administered twice daily
for treatment of acute bacterial conjunctivitis.
Methods: Two identically designed, double-masked, multicenter studies in the United States and India enrolled
patients 1 year or older with acute bacterial conjunctivitis. Patients were randomized to gatifloxacin 0.5% or
vehicle treatment for 5 days. Clinical success in clearing conjunctival hyperemia and discharge at day 6
(primary endpoint) and day 4 and microbiological cure were determined. Isolates from positive conjunctival
samples were tested for sensitivity and susceptibility. Safety measures included adverse events (AEs). Data
from these 2 studies were pooled for these analyses.
Results: Of the 1437 randomized patients, 658 constituted the modified intent-to-treat population. Patient char-
acteristics were similar between the pooled treatment groups. Clinical success occurred for 58.0% of gatifloxacin
0.5%-treated versus 45.5% vehicle-treated patients at day 6 (P = 0.001) and for 23.7% versus 15.4% in the
respective groups at day 4 (P = 0.007). Microbiological cure was higher with gatifloxacin 0.5% than vehicle at
days 4 and 6 (P < 0.001 for both time points). The combined minimum inhibitory concentration required to inhibit
90% of isolates for gatifloxacin 0.5% was 2.0 mg/mL for gram-positive and gram-negative organisms. AEs were
reported by 11.6% and 13.3% of patients in the gatifloxacin 0.5% and vehicle safety populations, respectively. One
patient in each treatment group experienced a serious AE; neither was treatment related.
Conclusions: The 0.5% concentration of gatifloxacin ophthalmic solution was safe and effective for treatment
of acute bacterial conjunctivitis with twice-daily administration for 5 days.

Introduction inability to collect specimens, inadequacy of specimens, and

B acterial conjunctivitis, a common infection of the
ocular surface that affects individuals of all ages, typically
presents with erythema, mucopurulent discharge, and che-
mosis.1,2 Staphylococcus species, Streptococcus pneumonia,
and Haemophilus influenza are the most prevalent causa-
tive bacteria in adults, and H. influenza, S. pneumonia, and
Moraxella catarrhalis infections are most frequently reported
in children.3,4 Based on the course and severity, bacterial
conjunctivitis is typically categorized into hyperacute, acute,
and chronic forms. Acute conjunctivitis is often defined as
conjunctivitis with symptoms lasting 3 to 4 weeks.5 Incidence
and prevalence rates are difficult to ascertain owing to the
spontaneous remission before diagnosis.6 Collectively, acute
conjunctivitis (bacterial, viral, and allergic) is estimated to
account for 1% to 4% of all visits to the primary care phy-
sician in the developed world.7–10
Although it is often a self-limiting disease, approximately
70% of patients with acute conjunctivitis seek treatment at
primary and urgent care centers in the United States.11 Em-
pirical treatment with topical antibacterial agents that have a
broad spectrum of activity against both gram-positive and gram-
negative bacteria is the standard of care for acute bacterial
conjunctivitis.12 Meta-analyses have shown that topical antibi-
otic treatment can shorten the disease course, reduce likeli-
hood of relapse, and decrease the risk of vision-threatening

1
Arizona Center for Clinical Trials, Phoenix, Arizona.
2
Premier Health Research Center, Downey, California.
3
St. George’s Hospital, Mumbai, India.
4
J&L De Leon Medical Corp, Paramount, California.
5
Allergan, Inc., Irvine, California.

815
816
complications such as keratitis.12,13 Topical fluoroquinolones
are active against bacteria that commonly cause conjunctivitis.
However, older fluoroquinolones have been associated with
ocular pathogen resistance.14–16
Antibacterial resistance is an inevitable consequence of
the selective pressure of antibiotic exposure that is becom-
ing prevalent among common bacterial causes of infections,
including ocular infections.17 Cavuoto et al. reported a 2-
fold increase in the resistance of gram-positive organisms to
ciprofloxacin from patients with bacterial conjunctivitis from
1994 to 2003.18 More recently, Adebayo et al. reported a
6-fold increase in resistance to ciprofloxacin for both gram-
positive and gram-negative isolates based on records of pa-
tients with bacterial conjunctivitis from 1997 to 2008.4 An
increasing frequency of methicillin-resistant Staphylococcus
aureus (MRSA) among ocular isolates is of particular concern.
Population-based surveillance studies indicate that MRSA in-
fections are no longer confined to hospitals or hospital workers
and can be acquired from the community.19,20 In the United
States, the incidence of MRSA infections steadily increased
from 29.5% in 2000 to 41.6% in 2005.21 Among patients with
bacterial conjunctivitis, the frequency of MRSA isolates sig-
nificantly increased from 0.05% in 1994 to 30.5% in 2003.18
Most MRSA are multidrug resistant ( ‡ 3 antibiotic agents),21
and antibacterial-resistant infections may be more difficult to
treat resulting in more serious complications. With continued
increase in bacterial resistance, there is a need for effective
antibacterial agents, such as a newer generation or formulations
of fluoroquinolones, to treat ocular bacterial infections poten-
tially caused by more resistant organisms.
Gatifloxacin ophthalmic solution 0.3% (Zymar; Allergan,
Inc., Irvine, CA), a fourth-generation fluoroquinolone, has
been used successfully as a 4-times-a-day treatment of bac-
terial conjunctivitis.22 Fluoroquinolones are concentration-
dependent antibacterial agents23; therefore, increasing the
concentration of gatifloxacin may improve efficacy. In addi-
tion, enhancing the antibacterial activity of gatifloxacin 0.3%
also may help prevent selection of resistant mutants. The ga-
tifloxacin ophthalmic solution 0.5% (Zymaxid; Allergan,
Inc.) is a new formulation of gatifloxacin that was developed
to maintain the safety of the prior formulation, while en-
hancing efficacy and allowing flexibility for a less frequent
dosing regimen. Two large multicenter clinical trials that
evaluate the efficacy and safety of gatifloxacin 0.5% oph-
thalmic solution in patients 1 year of age or older with acute
bacterial conjunctivitis were designed and conducted to sup-
port regulatory approval. In this study, we report the pooled
results of those trials.
Methods
Study design
Two identically designed, randomized, multicenter, double-
masked, vehicle-controlled, phase 3 trials were conducted to
evaluate the efficacy and safety of gatifloxacin ophthalmic
solution 0.5% for the treatment of acute bacterial conjuncti-
vitis. The first trial was conducted between August 2007 and
June 2008 at 51 sites in the United States (ClinicalTrials.gov
identifier: NCT00509873), and the second was conducted
between February 2008 and January 2009 at 10 sites in the
United States and 29 sites in India (ClinicalTrials.gov identi-
fier: NCT00518089). Each study adhered to the tenets of the
HELLER ET AL.
Declaration of Helsinki and Good Clinical Practice guidelines
and was compliant with the Health Insurance Portability and
Accountability Act of 1996 for all the US sites. The study
protocol was approved by an institutional review board or
independent ethics committee at each site and all patients
provided written informed consent.
Study population
Patients at least 1 year of age were eligible for participation
if they were clinically diagnosed in one or both eyes with
acute bacterial conjunctivitis (or blepharoconjunctivitis), de-
fined as moderate to severe (grade 2–3) conjunctival hyper-
emia and mild to severe (grade 1–3) discharge, graded on a
4-point scale (0 = none, 1 = mild, 2 = moderate, 3 = severe).
Eligible patients must have had a best-corrected visual acuity
equivalent to Snellen acuity of 20/80 or better. For children
younger than 3 years old, visual acuity measurement was at
the discretion of the investigator.
Patients were excluded if they had used antibiotics or
corticosteroids for treatment of other infections during the
past 1 or 2 weeks, respectively, before study enrollment; had
signs and/or symptoms of conjunctivitis for more than 96 h
or suggestive of fungal, viral, chlamydial, or allergic eti-
ology; or were positive for adenovirus antigen using the
RPS Adeno Detector [Rapid Pathogen Screening, Inc.
(Williamsport, PA); K052092, November 2005] at baseline.
Patients also were excluded from the trials if they had a
clinical diagnosis of orbital cellulitis, preseptal cellulitis or
ulcerative keratitis, infectious blepharitis as the primary
cause of ocular hyperemia and discharge in the opinion of
the investigator, uncontrolled systemic disease, serious
systemic infection, immunosuppression, or known contra-
indications to any study medication component.
Patients may have had one eye or both eyes clinically di-
agnosed with acute bacterial conjunctivitis at day 1 (baseline)
and qualified to be treated. If both eyes were diagnosed with
acute bacterial conjunctivitis, the eye with positive bacterial
conjunctival culture at baseline was designated as the study
eye, while if both eyes were culture positive or negative at
baseline, the right eye was designated as the study eye.
Study randomization, intervention, and masking
On the day 1 visit, after completion of the baseline eye
examination, patients were assigned a randomization num-
ber sequentially, according to the order of enrollment within
each site. Blocks of computer-generated numbers allocated
to each site and a central, automated interactive voice
response system/interactive web response system (IVRS/
IWRS) were used for patient assignment. Patients were
randomized 1:1 to receive either gatifloxacin 0.5% or ve-
hicle (the formulation without gatifloxacin) in the qualified
eye(s) for 5 days. On day 1, patients instilled 1 drop of study
medication every 2 h for up to 8 doses. On days 2 to 5,
patients instilled 1 drop of study medication twice a day in
the qualified eye(s).
All study medication was supplied in identical sterile plastic
10-mL dropper bottles. The bottles had unit labels coded
at Allergan using a computer-generated randomization list,
which included the study number and kit number matching the
patient randomization assignments. Patients, all personnel
responsible for clinical management, laboratory staff, and
GATIFLOXACIN IN BACTERIAL CONJUNCTIVITIS
study administrators were masked to the randomized treat-
ment assignment throughout the study.
Visits were scheduled on day 1 (baseline), day 4, and day
6; the day 6 visit must have occurred between 12 h (mini-
mum) and 48 h (maximum) after the last dose of study
medication. At each visit, ocular signs (conjunctival hy-
peremia and mucopurulent discharge) and symptoms (itch-
ing and tearing) of conjunctivitis in both eyes were rated
using a 4-point scale (0 = none, 1 = mild, 2 = moderate,
3 = severe). Using conjunctival swabs, samples for deter-
mining bacterial culture and sensitivity were taken from the
clinically diagnosed eyes without the aid of topical anes-
thetic. The swabs were aseptically added to transport tubes
and prepared for shipment to a central laboratory. Adverse
events (AEs) were recorded, and visual acuity and biomi-
croscopy assessments were conducted in both eyes. At each
study visit, the clinical staff inspected the medication bottle
to confirm usage. Any major deviations from the adminis-
tration schedule (eg, medication was administered for less
than 5 days) were reported.
Microbiological sensitivity and susceptibility
Conjunctival samples with organisms above the in vitro
pathological threshold were tested for microbiological sen-
sitivity and susceptibility to gatifloxacin, moxifloxacin,
azithromycin, ciprofloxacin, erythromycin, gentamicin, tet-
racycline, and tobramycin. In addition, the Kirby-Bauer
measurement was used to test susceptibility to gatifloxacin
and moxifloxacin. Sampling kits, including transport media,
were provided to each site in the United States and India by
Covance Central Laboratories Services (Indianapolis, IN), a
laboratory certified by the College of American Pathology
(CAP) and with Clinical Laboratory Improvement Amend-
ments (CLIA) certification, to maintain uniform analytical
processes. Instructions for collection, storage, and transport
were provided to each site.
Conjunctival samples obtained at sites in the United States
were sent directly to Covance for all analysis, including
identification, quantification, and Kirby-Bauer testing. Con-
junctival samples obtained from sites in India were frozen and
shipped within 24 to 48 h, to Super Religare Laboratories
Limited (formerly SRL Ranbaxy Limited, Mumbai, India),
also CAP certified, which had received instructions on pro-
cessing organisms from Covance. SRL performed identifica-
tion, quantification, and Kirby-Bauer testing. Culture-positive
organisms, determined to be above the specific quantitative
threshold, were refrozen and sent in batches to Covance in the
United States for susceptibility and minimum inhibitory con-
centration (MIC) testing. The organism identification com-
pleted in India by SRL was used for the outcome analysis,
although the organisms were reidentified by Covance before
susceptibility testing.
MICs (mg/mL) were determined for organisms above the
pathological threshold at a given visit, and when multiple
numbers of any one species were observed, MIC90s (mini-
mum concentration required to inhibit 90% of isolates) were
calculated. Sensitivity and susceptibility criteria were deter-
mined using the active agent by standard methods, defined by
Clinical Laboratory Standards Institute (CLSI) Performance
Standards for Antimicrobial Susceptibility Testing M100-S17
(2007) and CLSI M45-A (methods for antimicrobial dilution
and disk susceptibility testing of infrequently isolated or
817
fastidious bacteria). MIC results from a single laboratory,
Covance, were used in data analysis for all sites.
Outcome measures and data analysis
All patients satisfying the inclusion criteria and clinically
diagnosed with bacterial conjunctivitis at baseline, who
were randomized and began treatment, comprised the intent-
to-treat (ITT) population. Efficacy endpoints that were
evaluated in the pooled modified intent-to-treat (mITT)
population, comprised patients whose conjunctival samples
collected from at least one of the qualified eye(s) at baseline
tested positive for bacterial cultures postrandomization. All
patients enrolled in the study who received at least 1 dose of
study medication were included in the safety analysis; all
qualified eyes were evaluated for safety assessments.
The prespecified primary efficacy endpoint for the pooled
analyses was clinical success at day 6 in the pooled mITT
population, defined as the proportion of patients with clearing
of both conjunctival hyperemia and discharge (score of 0 for
both) in the study eye using the up to day 6 analysis method.
Since the self-limiting course of bacterial conjunctivitis may
reduce observable differences between treatment groups at
later time points, data collected after day 6 were excluded to
identify treatment benefits that occurred before the resolution
of bacterial conjunctivitis. All secondary efficacy endpoints
were analyzed in the study eye and included clinical success
at day 4, the patients achieving microbiological cure (defined
as eradication of all bacteria present at baseline) at day 4 and
at any time up to and including day 6, and clinical im-
provements in ocular signs and symptoms. AEs recorded by
the investigator were coded to preferred terms using the
Medical Dictionary of Regulatory Activities, version 10.0.
The last observation carried forward method was used to
impute missing values for efficacy analyses of the mITT and
ITT populations. Categorical variables were analyzed by
the Pearson chi-square test, Fisher’s exact test, or Cochran–
Mantel–Haenszel method. Continuous variables were analyzed
using analysis of variance for between-group comparisons and
the paired t test for within-group analysis of changes from
baseline. A P value of £ 0.05 was considered a statistically
significant difference between treatment groups.
Power calculations for each of the individual studies in
this pooled analysis were based on a 2-sided Pearson chi-
square test for the primary efficacy measure using the
mITT population. Assuming clinical success in 57% of
patients in the vehicle group and a type-I error rate of 0.05,
a sample size of 140 patients per treatment group in the
mITT population was estimated to achieve 80% power to
detect a difference of 16 percentage points in clinical
success, between gatifloxacin 0.5% and vehicle. With an
expected 60% culture-positive rate, 467 patients were
projected to be randomized in each study to attain 280
patients (140 per treatment group assuming an equal dis-
tribution of positive cultures in each treatment group) for
the mITT population.
Results
Patient disposition and baseline characteristics
In total, 1437 patients were randomized in the two phase
3 studies; 1433 patients received at least 1 dose of study
818 HELLER ET AL.

FIG. 1. Patient disposition. aSeventy-two

randomized patients from 1 site were ex-
cluded from the intent-to-treat (ITT) pop-
ulation and efficacy analyses due to data
integrity issues. bModified ITT population
consisted of patients with a positive con-
junctival culture at baseline.

drug and constituted the safety population (Fig. 1). Seventy- receiving gatifloxacin 0.5% had clinical success compared
two patients from 1 site were excluded from all efficacy with 15.4% (50/325) in the vehicle group (P = 0.007) (Fig.
analyses due to data integrity issues. The United States Food 2A). At days 4 and 6, microbiological cure was greater
and Drug Administration was informed of the data integrity in the gatifloxacin 0.5% treatment group, with the difference
concerns and allowed the exclusion of these patients from between treatment groups being statistically significant.
the primary analysis. Consequently, the pooled ITT popu-
lation consisted of 1365 patients; 681 randomized to receive
gatifloxacin 0.5% (642 [94.3%] completed treatment) and Table 1. Patient Demographics and Baseline
684 randomized to vehicle (639 [93.4%] completed treat- Characteristics (mITT Population)
ment). The mITT population, the primary population for Gatifloxacin Vehicle
efficacy analyses, comprised 333 patients in the gatifloxacin Characteristic 0.5% (n = 333) (n = 325)
0.5% group and 325 patients in the vehicle group. Overall,
patient disposition was similar between the 2 treatment Age, n (%)
groups and the majority of patients completed the study as Mean (range), y 34.8 (1–89) 32.8 (1–88)
planned. 1–18 102 (30.6) 103 (31.7)
Baseline demographic and patient characteristics for the 19–65 178 (53.5) 189 (58.2)
mITT population are presented in Table 1. There were no > 65 53 (15.9) 33 (10.2)
significant differences between treatment groups in age, sex, Sex, n (%)
or race. Only a small difference in the severity of con- Female 162 (48.6) 151 (46.5)
junctival hyperemia at baseline was present between the Male 171 (51.4) 174 (53.5)
gatifloxacin 0.5% (2.3) and the vehicle group (2.2), although Race, n (%)
the difference was statistically significant (P = 0.021). The Asian 156 (46.8) 158 (48.6)
severity of mucopurulent discharge and ocular symptoms White 87 (26.1) 87 (26.8)
Hispanic 75 (22.5) 61 (18.8)
of discomfort was comparable between the treatment groups Black 13 (3.9) 13 (4.0)
at baseline. Other 2 (0.6) 6 (1.8)
Conjunctival hyperemia in study eye
Clinical outcome results Mean severity score ( – SD) 2.3 – 0.45a 2.2 – 0.42
Clinical success at day 6 (primary endpoint) occurred in Mucopurulent discharge in study eye
Mean severity score ( – SD) 1.9 – 0.64 1.9 – 0.64
58.0% (193/333) of patients treated with gatifloxacin 0.5%
compared with 45.5% (148/325) of the vehicle-treated group a
P = 0.021, one-way analysis of variance.
(P = 0.001). At the day 4 time point, 23.7% (79/333) of patients mITT, modified intent-to-treat; SD, standard deviation.
GATIFLOXACIN IN BACTERIAL CONJUNCTIVITIS
FIG. 2. Proportion of patients with clinical success (A)
and microbiological cure (B) in the study eye at day 4 and at
day 6 following treatment with gatifloxacin 0.5% ophthal-
mic solution or vehicle. *P = 0.007; **P £ 0.001; Pearson
chi-square test.
At day 4, microbiological cure occurred in 87.4% (291/333)
of patients in the gatifloxacin 0.5% group and 62.8% (204/
325) in the vehicle group, and 90.4% (301/333) and 70.2%
(228/325) had microbiological cure at day 6, respectively
(P < 0.001 for both day 4 and day 6) (Fig. 2B).
Clinical improvement in ocular signs occurred in a higher
proportion of patients in the gatifloxacin 0.5% group com-
pared with the vehicle group at both day 4 (92.8% [309/333]
vs. 87.1% [283/325]; P = 0.015) and day 6 (96.1% [320/333]
vs. 92.3% [300/325]; P = 0.037) time points. Improvements
in ocular symptoms in the study eye were recorded in the
gatifloxacin 0.5% treatment group compared with the ve-
hicle group at the day 4 (80.4% [267/332] vs. 74.1% [240/
324]) and day 6 (87.7% [291/332] vs. 84.3% [273/324])
time points, but did not reach statistical significance.
Microbiological results
Bacterial isolates commonly identified at baseline in the
mITT population are shown in Table 2; the most frequently
identified organisms in a qualified eye in the gatifloxacin
0.5% and vehicle groups overall were H. influenza (20.1%
and 17.5%), S. aureus (19.5% and 15.7%), Staphylococcus
epidermidis (16.5% and 15.7%), and S. pneumonia (13.8%
819
Table 2. Bacteria Isolated from ‡ 5% of Patients
in Either Treatment Group from Conjunctival
Samples Collected at Baseline from Qualified Eyes
Proportion of patients, n (%)
Gatifloxacin Vehicle
Bacteria organism 0.5% (n = 333) (n = 325)
Haemophilus influenza 67 (20.1) 57 (17.5)
Staphylococcus aureus 65 (19.5) 51 (15.7)
Staphylococcus epidermidis 55 (16.5) 51 (15.7)
Streptococcus pneumonia 46 (13.8) 45 (13.8)
Gram-positive cocci 13 (3.9) 22 (6.8)
Staphylococcus hominis 11 (3.3) 18 (5.5)
Pseudomonas aeruginosa 9 (2.7) 17 (5.2)
in both groups). The 5 most common organisms isolated in
at least 5 patients in the qualified eye at baseline in the
United States were H. influenza, S. pneumonia, S. aureus,
S. epidermidis, and the Streptococcus mitis group, with MIC90s
to gatifloxacin 0.5% ranging from 0.03 mg/mL to 2.0 mg/mL. In
India, the 5 most common organisms were S. aureus, S. epi-
dermidis, Staphylococcus hominis, Klebsiella pneumonia, and
Pseudomonas aeruginosa, with MIC90s to gatifloxacin 0.5%
ranging from 1.0 mg/mL to > 8.0 mg/mL.
The combined MIC90 of gatifloxacin 0.5% for all organisms
in any qualified eye was 2.0 mg/mL (Table 3). This was the
same as the MIC90 of moxifloxacin and lower than the MIC90s
for azithromycin, ciprofloxacin, erythromycin, gentamicin,
tetracycline, and tobramycin, which ranged from 8.0 mg/mL
to > 32 mg/mL. The MIC90 of gatifloxacin 0.5% for all gram-
positive bacteria combined was 2.0 mg/mL, which was the
same as the MIC90 of moxifloxacin and lower than the MIC90s
for azithromycin, ciprofloxacin, erythromycin, gentamicin,
tetracycline, and tobramycin, which ranged from > 8.0 mg/mL
to > 32 mg/mL. For gram-negative organisms, the combined
MIC90 of gatifloxacin 0.5% was 2.0 mg/mL, which was the
same as the MIC90 for tobramycin, higher than the MIC90 of
ciprofloxacin (0.50 mg/mL), and lower than the MIC90s for
moxifloxacin, azithromycin, erythromycin, gentamicin, and
tetracycline, which ranged from 4.0 mg/mL to > 32 mg/mL.
Safety results
Overall, treatment with gatifloxacin 0.5% was well tol-
erated, and the majority of AEs in both treatment groups
were of mild or moderate severity. Across the pooled
studies, there were 2 patients with serious AEs: one patient
in the gatifloxacin group with a history of depression and
anxiety who was hospitalized (for worsening depression and
anxiety) a day after starting medication and another patient
in the vehicle group who suffered congestive heart failure.
The incidence of all AEs regardless of causality for the
pooled safety population was low and numerically lower in the
gatifloxacin 0.5% (11.6% [83/717]) than in the vehicle group
(13.3% [95/716]), although the difference was not statistically
significant (P = 0.332). The incidence of treatment-related AEs
was 4.3% (31/717) in the gatifloxacin 0.5% group compared
with 3.4% (24/716) in the vehicle group (P = 0.338); only 2
treatment-related AEs, eye irritation and dysgeusia, were re-
ported by 1% or more of patients but occurred in less than 3%
of patients in any treatment group. AEs reported by 1% or
more of patients in any treatment group are shown in Table 4.
820 HELLER ET AL.

Table 3. Sensitivity of Bacteria Isolated from Conjunctival Samples Collected in Any Qualified Eye
at Baseline, by Bacterial Classification and for the Most Common Organisms (All Sites Combined)
Minimum inhibitory concentration (MIC90 in mg/mL)a
Antibacterial All organisms Gram-positive Gram-negative H. influenza S. aureus S. epidermidis S. pneumonia
drug (n = 964) (n = 672) (n = 292) (n = 185) (n = 130) (n = 119) (n = 134)
Gatifloxacin 2.00 2.00 2.00 0.03 4.00 2.00 0.25
Moxifloxacin 2.00 2.00 4.00 0.06 2.00 4.00 0.12
Ciprofloxacin 8.00 > 8.00 0.50 0.02 > 8.00 > 8.00 1.00
Gentamicin 16.00 16.00 4.00 2.00 64.00 32.00 16.00
Tobramycin 32.00 32.00 2.00 2.00 > 32.00 16.00 32.00
Azithromycin > 32.00 > 32.00 > 32.00 2.00 > 32.00 > 32.00 32.00
Erythromycin > 16.00 > 16.00 > 16.00 8.00 > 16.00 > 16.00 16.00
Tetracycline 32.00 32.00 16.00 0.50 1.00 > 64.00 32.00
a
Sensitivity testing conducted for organisms above pathological threshold only and treatment groups were combined.
MIC90, minimum concentration required to inhibit 90% of isolates.

There were no changes in visual acuity or biomicroscopy diagnosed eye(s). On the first day of treatment, a drop was to
finding increases of 1 severity grade or greater from baseline to be administered every 2 h up to 8 times. Thereafter, dosing
any follow-up visit, which occurred at a significantly greater every 12 h was expected to be sufficient to kill the remaining
frequency in the gatifloxacin 0.5% group than the vehicle group. bacteria, even those with a low level of resistance to the
anti-infective. With reported increases in antibacterial re-
Discussion sistance with ocular pathogens, including those that cause
bacterial conjunctivitis,4,18 it is important that antibacterial
Acute bacterial conjunctivitis is one of the most com- ophthalmic solutions eliminate all bacterial isolates to help
mon eye disorders encountered by primary care physicians prevent the development of resistant variants.
and urgent care centers.5,24 Results from this study suggest The fourth-generation fluoroquinolones, gatifloxacin and
that gatifloxacin 0.5% ophthalmic solution administered moxifloxacin, were introduced to provide greater coverage
twice daily for up to 5 days is effective for the treatment of against gram-positive organisms than earlier generations of
acute bacterial conjunctivitis in patients 1 year of age or fluoroquinolones, based on significant activity against both
older. Gatifloxacin 0.5% was superior to vehicle treatment DNA gyrase and topoisomerase IV.25,26 Susceptibility test-
in the primary analysis; clinical success was achieved in ing from the current studies revealed that gatifloxacin 0.5%
the study eye at the day 6 time point using the up to day 6 had an overall MIC90 of 2.0 mg/mL among all bacterial
analysis method in the pooled mITT population. Gati- isolates from conjunctival samples collected at baseline
floxacin 0.5% was also superior to vehicle treatment on the (day 1). For all gram-positive organisms tested, the MIC90
secondary efficacy variables of clinical success at the day 4 of gatifloxacin was similar to that for moxifloxacin and
time point and for both microbiological cure and clinical lower than all other antimicrobial agents. For all gram-
improvement in ocular signs at the day 4 and day 6 time negative organisms, the MIC90 for gatifloxacin was similar
points. to tobramycin and lower than all other antimicrobials tested
Gatifloxacin 0.5% was administered twice daily to pa- except ciprofloxacin, which had the lowest MIC90. Overall,
tients with acute bacterial conjunctivitis in this study. For ciprofloxacin, a second-generation fluoroquinolone, had
products of this type, it is a typical practice to start treatment significantly lower potency relative to both gatifloxacin and
with a loading dose to kill a majority of the bacteria in the moxifloxacin for gram-positive organisms. This is consistent
with a previous in vitro study that found gatifloxacin and
moxifloxacin to be superior to ciprofloxacin against gram-
Table 4. Nontreatment and Treatment-Related positive organisms, and ciprofloxacin to be most effective
Adverse Events Occurring in ‡ 1% against gram-negative organisms from ocular infections.27 In
of Patients in Either Treatment Group another study of bacterial isolates from ocular infections, a
higher percentage of both gram-negative and gram-positive
Gatifloxacin Vehicle organisms were susceptible to gatifloxacin compared to
Adverse event, n (%) 0.5% (n = 717) (n = 716)
other topical antibiotics, including ofloxacin, ciprofloxacin,
All adverse events 83 (11.6) 95 (13.3) norfloxacin, gentamicin, tobramycin, neomycin, chloram-
Bacterial conjunctivitis 19 (2.6) 32 (4.5) phenicol, erythromycin, tetracycline, and amikacinin.28 As
Eye irritation 15 (2.1) 8 (1.1) has been reported in other studies,3,4 the most common
Dysgeusia 8 (1.1)a 1 (0.1) organisms identified at baseline were H. influenza, S. aureus, S.
Eye pain 7 (1.0) 9 (1.3) epidermidis, and S. pneumonia. Despite the different causative
Conjunctivitis 2 (0.3) 9 (1.3)b organisms, microbiological cure was observed with gati-
Treatment-related adverse events 31 (4.3) 24 (3.4) floxacin 0.5% ophthalmic solution in nearly all patients
Eye irritation 15 (2.1) 7 (1.0) enrolled in the study.
Dysgeusia 8 (1.1)a 1 (0.1)
Overall, treatment with gatifloxacin 0.5% ophthalmic
a
P < 0.04, Fisher’s exact test. solution was safe and well tolerated. There were no differ-
b
P < 0.05, Pearson’s chi-square test. ences in the incidence of general or ocular AEs between the
GATIFLOXACIN IN BACTERIAL CONJUNCTIVITIS
gatifloxacin 0.5% and vehicle groups. The most frequently
reported treatment-related AEs in either group were eye
irritation and dysgeusia.
The study has some limitations, including comparing
gatifloxacin 0.5% to vehicle treatment and not an active
comparator, and both gatifloxacin 0.5% and vehicle prod-
ucts contained the preservative benzalkonium chloride
that has antibacterial activity and may have affected out-
comes.29–31 In addition, all conjunctival samples collected
from patients across the study sites were shipped to an in-
dependent central laboratory in Indiana for susceptibility
testing. Other studies have employed a similar design, in-
cluding the Ocular Tracking Resistance in US Today
(TRUST) study, a nationwide study involving 35 sites
evaluating the antimicrobial susceptibility patterns in the
United States.32
Conclusions
Based on clinical success (defined as the proportion of
patients with a score of zero for both conjunctival hyperemia
and discharge at day 6), gatifloxacin 0.5% ophthalmic so-
lution administered twice daily for 5 days was effective in
treating acute bacterial conjunctivitis in patients enrolled at
sites in both the United States and India. Microbiological
cure was achieved with gatifloxacin 0.5% regardless of the
wide variety of bacterial isolates and susceptibilities iden-
tified in vitro at baseline. No significant safety issues related
to the study drug were observed with gatifloxacin 0.5% ei-
ther in adults or in pediatric patients.
Acknowledgments
This study was sponsored by Allergan, Inc. (Irvine, CA).
Writing and editorial assistance were provided to the authors
by Kakuri Omari, PhD, and Gayle Scott, PharmD, of Evi-
dence Scientific Solutions (Philadelphia, PA), and funded by
Allergan, Inc. (Irvine, CA). All authors met the ICMJE
authorship criteria. Neither honoraria nor payments were
made for authorship.
Author Disclosure Statement
W.H., M.C., Y.R.B., and J.M.D. have no competing
conflicts of interest; C.F., L.V., D.A.H., and H.J. are em-
ployees of Allergan, Inc. (Irvine, CA).
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Received: April 8, 2014
Accepted: July 29, 2014
Address correspondence to:
Dr. Harold Jensen
Allergan, Inc.
2525 Dupont Drive
Irvine, CA 92623
E-mail: harold_jensen@allergan.com
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